PIAS1 loss and INHBA gain define a TGFβ-driven EMT state in OSCC progression

Oral squamous cell carcinoma (OSCC), a highly aggressive subtype of head and neck cancer, remains a major clinical challenge with limited therapeutic options and poor survival outcomes. The Protein Inhibitor of Activated STAT1 (PIAS1), a SUMO E3 ligase involved in transcriptional regulation, DNA repair, and epithelial-mesenchymal transition (EMT), exhibits cancer type-specific roles, but its function in OSCC has not been well characterized. Here, we investigated the molecular and functional role of PIAS1 in OSCC progression and prognosis. All patient cohorts analysed here comprise HPV-negative disease. Analysis across multiple cohorts revealed that PIAS1 mRNA expression is significantly lower in tumor tissues than in normal oral cavity squamous epithelium, including in a cohort of 60 patient-matched tumor and normal pairs. Within the tumor compartment, protein abundance of PIAS1 correlated positively with patient survival. Functional assays using OSCC cell lines demonstrated that PIAS1 acts in a SUMO E3-dependent manner to suppress TGF{beta}-induced migration and invasion. Transcriptomic profiling of PIAS1-depleted cells revealed alterations in expression of genes with relevance in TGF{beta} signaling and pro-invasive cellular responses. Further analyses showed that 46 of these differentially altered hits intersected with The Cancer Genome Atlas (TCGA)-OSCC datasets, where four of these genes, including INHBA, associated with cell stemness-pathway. Spatial analysis of the mRNA abundance of INHBA within OSCC-derived surgical specimens showed increased abundance at the invasive front, and positively associated with aggressive tumor phenotypes, poor patients' outcomes, and resistance to immunotherapy. Single-cell RNA-seq analyses of INHBA revealed increased levels within tumor cells and cancer-associated fibroblasts (CAFs), suggesting potential tumor-intrinsic and extrinsic (tumor microenvironment) sources and hence actions. Collectively, our findings establish PIAS1 as a tumor suppressor in OSCC that restrains TGF{beta}-driven aggressive behaviour. Furthermore, we identify INHBA as a potential therapeutic target, among other genes characterized by spatially restricted, invasive tumor phenotypes.